Single-cell dissection of regulated cell death dynamics in ovarian aging

Ovarian aging drives declining fertility, premature menopause, and systemic age-related diseases. Multiple different types of regulated cell death (RCD) pathways have been identified and play integral roles in diverse physiological and pathological processes. However, the RCD landscape of ovarian aging remains uncharacterized at single-cell resolution. Here, we conducted single-cell RNA sequencing (scRNA-seq) on murine ovaries across aging (3, 9, 12 and 15 months), and mapped pan-RCD dynamics, including apoptosis, ferroptosis, parthanatos, and ten other pathways, revealing cell-type-specific RCD trajectories. These pathways exhibited distinct changes with ovarian aging, highlighting cell heterogeneity. Notably, apoptosis and parthanatos pathways demonstrated high correlations and rates of change with advancing age. Parthanatos was particularly notable for exhibiting one of the steepest age-associated increases. Cross-species validation using human ovarian scRNA-seq and GTEx V8 transcriptomics confirmed conserved parthanatos upregulation with age, negatively correlating with the expression levels of key enzymes in hormone synthesis. The study deciphers the RCD patterns in murine and human ovarian aging, nominating parthanatos as a targetable node for combating ovarian aging and enhancing female fertility.